Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection
Fanny Tzelepis, Mark Verway, Jamal Daoud, Joshua Gillard, Kimya Hassani-Ardakani, Jonathan Dunn, Jeffrey Downey, Marilena Elena Gentile, Joanna Jaworska, Anthony Michel Jean Sanchez, Yohann Nédélec, Hojatollah Vali, Maryam Tabrizian, Arnold Scott Kristof, Irah Luther King, Luis Bruno Barreiro, Maziar Divangahi
Fanny Tzelepis, Mark Verway, Jamal Daoud, Joshua Gillard, Kimya Hassani-Ardakani, Jonathan Dunn, Jeffrey Downey, Marilena Elena Gentile, Joanna Jaworska, Anthony Michel Jean Sanchez, Yohann Nédélec, Hojatollah Vali, Maryam Tabrizian, Arnold Scott Kristof, Irah Luther King, Luis Bruno Barreiro, Maziar Divangahi
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Research Article Infectious disease

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection

Abstract

The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen–presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen–specific CD8+ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte–derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to Mtb infection and mediates the power of DC efferocytosis and cross-presentation.

Authors

Fanny Tzelepis, Mark Verway, Jamal Daoud, Joshua Gillard, Kimya Hassani-Ardakani, Jonathan Dunn, Jeffrey Downey, Marilena Elena Gentile, Joanna Jaworska, Anthony Michel Jean Sanchez, Yohann Nédélec, Hojatollah Vali, Maryam Tabrizian, Arnold Scott Kristof, Irah Luther King, Luis Bruno Barreiro, Maziar Divangahi

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Figure 7

Annexin1 regulates cross-presentation in DCs.

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Annexin1 regulates cross-presentation in DCs. (A and B) DCs were purifie...
(A and B) DCs were purified from spleen and lymph nodes of WT or Anxa1–/– mice, and cultured with irradiated B2m–/– splenocytes, as indicated, that were either untreated (+B2m–/– –OVA) or loaded with 10 mg/ml soluble OVA (+B2m–/– +OVA). As a positive control, DCs were loaded with 1 μM OVA peptide without B2m–/– splenocytes (–B2m–/– +SIINFEKL). CFSE-labeled OT-I CD8+ T cells were cultured with these cells, and T cell proliferation was determined by flow cytometry at day 3. Numbers above gate (A) indicate the percentage of CFSElo cells. Results are representative of 2 independent experiments. **P < 0.01 (t test). (C and D) DCs were purified from spleen and lymph nodes of WT or Anxa1–/– mice and loaded with 2 μg/ml of OVA protein for 4 hours at 37°C or SIINFEKL. After washes, CFSE-labeled OT-I CD8+ T cells were cultured with these cells for 3 days and T cell proliferation was determined by flow cytometry. Numbers above gate (C) indicate the percentage of CFSElo cells. **P < 0.01 (t test).